Nitric oxide (the chemical formula is NO) is a remarkable small molecule that is vitally important in many biological processes. It is a vasodilator that increases blood flow through arteries and veins, and is also an important factor in controlling/preventing platelet adhesion and aggregation and thrombus formation. It also plays a crucial role in the immune system and in neurotransmission. Much is now known about the mode of action of nitric oxide and it is clear that it has enormous potential in medicine and biotechnology in both in vivo and ex vivo applications.
The controlled delivery of nitric oxide may be important in prophylactic and therapeutic procedures and application. For example, nitric oxide can prevent thrombosis and restenosis following balloon angioplasty and stent insertion in blocked arteries (International Patent Application WO 95/24908). Because nitric oxide is active in many biological processes, targeted delivery is desirable however. The delivery of nitric oxide to the skin may also have therapeutic benefits for patients with peripheral circulatory problems which can occur in conditions such as arthritis and Raynaud's syndrome. Nitric oxide also exhibits antibacterial properties and incorporation into antibacterial devices and use for the treatment of bacterial infections is desirable. Nitric oxide also plays a part in wound healing and angiogenesis, and delivery of nitric oxide to wounds and ulcers can be beneficial when healing is slow which can occur, for example, in elderly patients (M. Shabani et al, Enhancement of wound repair with a topically applied nitric oxide-releasing polymer Wound repair and regeneration, 4, 353, 1996 and S. Frank H. Kampfer, C. Wetzler, J. Pfeilschifer, Nitric oxide drives skin repair: Novel functions of an established mediator Kidney International, 61, 882, 2002).
However the delivery of nitric oxide to the desired area, and in the required optimum dose is often difficult because nitric oxide is a gas. Delivery of nitric oxide is difficult in both ex vivo e.g. biotechnology applications and in vivo e.g. medical applications.
Various methods of nitric oxide delivery are known such as                (a) molecules which release NO spontaneously;        (b) molecules which are metabolised to give NO;        (c) molecules that release NO on photoactivation;        (d) release of NO from polymers and polymer coatings;        (e) production of NO from a chemical reaction.        
The class (a) molecules include molecules known as nitric oxide nucleophile complexes (NONOates) (C. M. Maragos et al, Complexes of NO with nucleophiles as agents for the controlled biological release of nitric-oxide-vasorelaxant effects J. Med. Chem, 34, 3242, 1991). These are a variety of molecules which give off nitric oxide spontaneously and have been shown to have a possible use in therapeutic applications (U.S. Pat. No. 4,954,526). However the use of NONOates in therapy is limited because they become distributed throughout the body which may compromise selectivity. The by-products following the release of NO may also form carcinogenic secondary nitrosamines. Other class(a) molecules include nitrosothiols (Megson, I. L., Greig, I. R., Butler, A. R., Gray, G. A. & Webb, D. J. Therapeutic potential of S-nitrosothiols as nitric oxide donor drugs Scot. Med. J. 42, 88, (1997)). Also, the class(a) molecules may cause dangerous lowering of systemic blood pressure.
The class (b) molecules include glyceryl trinitrate and sodium nitroprusside (L. J. Ignarro Biosynthesis and metabolism of endothelium-derived nitric-oxide Ann. Rev. Pharmacol. Toxicol. 30, 535, 1990). These compounds are currently widely used as vasodilators, however prolonged use can lead to toxic side products such as cyanides. Furthermore, tolerance can be displayed because these molecules need to be metabolised to release NO. The targeting of NO to particular sites may also be poor resulting in the effects tending to be systemic.
The class (c) molecules require specific activation, for example, light having a specific wavelength which can be difficult to initiate (C. Works, C. J. Jocher, G. D. Bart, X. Bu, P. C. Ford, Photochemical Nitric Oxide Precursors Inorg. Chem., 41, 3728, 2002).
Class (d) release of nitric oxide mitigates the problems associated with systemic activity by delivering nitric oxide to a specific target site by supporting a nitric oxide releasing compound on a solid article. Such NO releasing compounds may be polymeric materials which can be coated onto medical instruments which can be used to target specific areas of the body for treatment. The polymers may contain, for example, the N2O2 group that releases NO after a chemical reaction (International Patent Application WO 95/24908 and US Patent Application 2002094985). However, the release of NO in such circumstances can be difficult to control and currently the preparation of the required materials may be expensive, often requiring multi-step processes and presenting difficult storage problems because of instability at room temperature and require storage at a cold temperature. The possible use of such polymers has been shown in the treatment of cardiovascular problems, for example, restenosis; the manufacture of anti-thrombogenic medical devices; alleviation of abnormal vasconstriction in the blood supply of the skin (Reynaud's syndrome) and for wound healing.
Class (e) delivery of nitric oxide has been proposed for topical applications by releasing nitric oxide from a chemical reaction. The chemical reaction involves the application of sodium nitrite, ascorbic acid and maleic acid, which gives off NO when contacted by water (U.S. Pat. No. 6,103,275). However, this reaction takes place only in acidic conditions and so may cause irritation, especially to sensitive skin of elderly patients. Additionally, the nitric oxide is released as a short-lived burst rather than in a controlled manner.
The object of the present invention is to obviate and/or mitigate the problems of nitric oxide storage and delivery.